Abstract: Complement factor H (CFH), a key regulator of the complement system, plays an integral role in the pathogenesis of age-related macular degeneration (AMD), the most common cause of blindness in developed countries. CFH knockout (KO) mice and other rodent models have provided many insights into the pathogenesis of AMD. However, these models are of limited value, especially for translational studies, given the significant differences in retinal anatomy and biology between humans and rodents (e.g., the latter lack maculae). Non-human primates (NHP) are superior models of human diseases, especially retinal diseases, because of the close physiological and anatomical similarities between NHP and humans (e.g., NHP are the only animals with maculae). However, despite recent technology advances, it remains technically and ethically challenging to generate gene-engineered NHP-based disease models. Our results from preliminary studies suggest the existence of naturally occurring CFH-deficient monkeys. Therefore, a combination of detailed assays of complement function, genomic sequencing, and analyses of non-invasive retinal imaging and functional parameters should allow us to identify and develop CFH-deficient monkeys as new models for AMD. This project will combine the respective expertise of three collaborative teams, including the Lin Lab at Cleveland Clinic (complement biology), the Chen Lab at Baylor College of Medicine (non-human primate genetics), and the Thomasy Lab at UC Davis (non-invasive NHP retinal imaging and function analyses) to achieve our short-term goal of identifying breeding monkeys harboring deficiencies in CFH (or other complement components). Ultimately, we aim to develop novel NHP AMD models that will enable the development of novel therapeutics (e.g. regenerative medicine and gene therapy) for this devastating blinding disease.